The hair follicle is an epidermal derivative that undergoes cycles of growth (anagen), involution (catagen), and rest (telogen). Although the mechanisms underlying hair cycling have not been fully elucidated, the core of the process involves interactions between the mesenchymal and epithelial cell populations within the hair follicle unit (Jahoda, C. A. & Reynolds, A. J. (1996) Dermatol. Clin. 14, 573–583). The most obvious regulator of the cycle is the papillary mesenchyme, in particular the dermal papilla.
Factors from the papillary mesenchyme act as inductive signals for cycling of the follicular epithelium (Peus, D. & Pittelkow, M. R. (1996) Dermatol. Clin. 14, 559–572). In particular, it has been inferred that epithelial stem cells, which reside in the bulge area of the hair follicles, can respond to the inductive signals from the dermal papilla and become activated (Cotsarelis, G., Sun, T. T. & Lavker, R. M. (1990) Cell 61, 1329–1337). This activation leads to proliferation of stem cells in the bulge area, and then the stem cell progeny forms a downgrowth into the deep dermis, followed by differentiative growth of matrix cells and generation of the complex follicular product, the shaft, and its housing sheath.
Analyses of the skin phenotypes of a considerable number of transgenic or gene knockout mice have shed light on the mesenchymal (dermal papilla) and epithelial (keratinocyte) interactions involved in the morphogenesis of hair follicles in the fetus (Gat, U. et al. (1998) Cell 95, 605–614; Chiang, C. et al. (1999) Dev. Biol. 205, 1–9; Botchkarev, V. A. et al. (1999) Nat. Cell Biol. 1, 158–164). The mechanisms underlying the biological switching process in postnatal follicles occurring between telogen and anagen, however, have remained unclear. The most likely candidate for factors inducing such switching is KGF-2, because KGF-2 is found in dermal papilla fibroblasts and its receptor, FGFR2IIIb, is found in neighboring keratinocytes (Katsuoka K., Schell H., Hornstein O. P., Wessel B. (1987) Br. J. Dermatol Mar 116(3), 464–5).
The kgf-2 (fgf-10) gene is a member of the fibroblast growth factor (referred to hereinfter as “FGF”) gene family comprising more than 22 genes in mammals (Nishimura T., Nakatake Y., Konishi M., Itoh N. (2000) Biochim. Biophys. Acta. 1492, 203–206). The FGF proteins are thought to regulate cellular proliferation, differentiation, migration, and survival by binding to and activating members of a family of tyrosine kinase receptors, i.e. FGF receptors (FGFRs). Among the 22 known FGF proteins, KGF-2 is structurally most related to FGF-7 (Miki T. et al. (1991) Science 251, 72–75 ; Ornitz D. M. et al. (1996) J. Biol. Chem. 271, 15292–15297 ; Igarashi M. et al. (1998) J. Biol. Chem. 273, 13230–13235), and both FGFs specifically bind to one isoform out of four FGFRs, i.e. FGFR2IIIb (Miki T. et al. (1991) Science 251, 72–75 ; Ornitz D. M. et al. (1996) J. Biol. Chem. 271, 15292–15297 ; Igarashi M. et al. (1998) J. Biol. Chem. 273, 13230–13235).
Functionally, KGF-2 has been shown to be involved in outgrowth of the limb bud and branching morphogenesis of the lung (Martin G. R. (1998) Genes Dev. 12, 1571–15869). The limb and lung buds are typical examples of organprimordia, which require intimate epithelial-mesenchymal interactions during development.
In epithelial-mesenchymal interactions, signals from the mesenchyme direct epithelial components to generate specific structures through budding or branching morphogenesis, and reciprocal interactions between the two tissues must be maintained during further development.
U.S. Pat. Nos. 5,184,605, 5,824,643 and 5,965,530 discuss the role of KGF-1 in the stimulation of proliferation, growth and differentiation in various cells of epithelial tissue, besides keratinocytes. It is thought that KGF-1 may be used as a therapeutic agent for the specific treatment of disease states and medical conditions afflicting tissues and organs such as the dermal adnexae, the liver, the lung and the gastrointestinal tract. The dermal adnexae include sebaceous glands, sweat glands and hair follicles.
The re-epithelialization activity of KGF has only been observed in dermis having an induced wound. The use of KGF for treatment of inherited alopecia is not taught or suggested by any of the above references.
Ruben et al., U.S. Pat. No. 6,077,692, disclose a newly identified KGF-2 which exhibits biological activities such as wound healing, anti-inflammatory effects, stimulation of differentiation and proliferation of liver cells and protection against lung damage. However, there is no experimental data regarding the effect of KGF-2 on the proliferation of hair follicle cells.